Abstract

Understanding the fundamental alterations in brain functioning that lead to psychotic disorders remains a major challenge in clinical neuroscience. In particular, it is unknown whether any state-independent biomarkers can potentially predict the onset of psychosis and distinguish patients from healthy controls, regardless of paradigm. Here, using multi-paradigm fMRI data from the North American Prodrome Longitudinal Study consortium, we show that individuals at clinical high risk for psychosis display an intrinsic "trait-like" abnormality in brain architecture characterized as increased connectivity in the cerebello-thalamo-cortical circuitry, a pattern that is significantly more pronounced among converters compared with non-converters. This alteration is significantly correlated with disorganization symptoms and predictive of time to conversion to psychosis. Moreover, using an independent clinical sample, we demonstrate that this hyperconnectivity pattern is reliably detected and specifically present in patients with schizophrenia. These findings implicate cerebello-thalamo-cortical hyperconnectivity as a robust state-independent neural signature for psychosis prediction and characterization.

Network alteration observed in the NAPLS-2 data. a The identified network with higher connectivity in converters and non-converters compared with controls from the NBS analysis. The nodes in the network mapped to seven functional systems (SM sensorimotor, VIS visual, AUD auditory, DMN default-mode, FPN frontoparietal, ATT attentional, SC-CRB subcortical-cerebellar). b Significant linear relationship was shown for the mean cross-paradigm connectivity of the identified network between three groups, with the converter group having the highest value and the control group having the lowest. Note that the cross-paradigm connectivity values were defined at the PCA space, which was rescaled to be mean centered at zero. CHR-C converters, CHR-NC non-converters, HC healthy controls. c The functional connectivity strength of the identified network in the original connectivity matrices for three groups. Significant effects were shown for all five paradigms (RS resting state, WM working memory, EMenc episodic memory encoding, EMret episodic memory retrieval, FM emotional face matching). d The mean cross-paradigm connectivity of the network was significantly correlated with the SOPS disorganization scores in subjects at clinical high risk but not in healthy controls. e The mean cross-paradigm connectivity of the network significantly predicted time to conversion to psychosis among converters. Error bars indicate standard errors

The presence of the observed network alteration in the CNP data. a Significant group differences were shown for the mean cross-paradigm connectivity of the identified network, which was driven by the differences between schizophrenia and controls. SZ schizophrenia, BD bipolar disorder, ADHD attention deficit hyperactivity disorder, HC healthy control. b The network alteration was significantly correlated with scores of SAPS thought disorder subscale in patients with schizophrenia. c Receiver operating characteristic curve for distinguishing patients with schizophrenia from healthy controls. The area under curve was significantly higher than that can be achieved by chance, per permutation testing. Error bars indicate standard errors